Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation

Tsoukas, Paul; Rapp, Emily; Kraak, Lauren Van Der; Weiss, Eric S.; Dang, Vinh; Schneider, Corinne; Klein, Edwin; Picarsic, Jennifer; Salcedo, Rosalba; Stewart, Charles A.; Canna, Scott

doi:10.1182/blood.2019003846

Cited by 32 publications

(19 citation statements)

References 55 publications

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“…49 More recent evidence suggests that perforin may play a critical immunoregulatory role, even in the absence of infection, in the context of chronic exposure to IL-18. 50 FHL typically requires biallelic mutations that profoundly impact cytotoxic function. Mutations that cause FHL when homozygous appear to be well tolerated by most heterozygous carriers.…”

Section: Impaired Cytotoxic Functionmentioning

confidence: 99%

“…93 Nevertheless, animal models support amplification of type 1 inflammatory responses as IL-18's pathomechanism in MAS, and suggest that the interaction of IL-18 and cytotoxic impairment may be particularly dangerous. 50,81,94 Clinical correlates of excess IL-18. Serum total IL-18 is available clinically and has demonstrated utility in distinguishing SJIA and MAS from other CSSs such as Kawasaki disease and FHL.…”

Section: Therapeutic T-cell Activation In Cancermentioning

confidence: 99%

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Highways to hell: Mechanism-based management of cytokine storm syndromes

Canna

Cron

2020

Journal of Allergy and Clinical Immunology

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Since the first textbook devoted to Cytokine Storm Syndromes (CSS) was published in 2019, the world has changed dramatically and the term’s visibility has broadened. Herein, we define CSS broadly to include life/organ-threatening systemic inflammation and immunopathology regardless of the context in which it occurs, recognizing that the indistinct borders of such a definition limit its utility. Nevertheless, we are focused on the pathomechanisms leading to CSS, including impairment of granule-mediated cytotoxicity, specific viral infections, excess IL-18, and Chimeric Antigen Receptor (CAR) T-cell therapy. These mechanisms are often reflected in distinct clinical features, functional tests, and/or biomarker assessments. Moreover, these mechanisms often indicate specific, definitive treatments. This mechanism-focused organization is vital to both advancing the field and understanding the complexities in individual patients. However, increasing evidence suggests these mechanisms interact and overlap. Likewise, the utility of a broad term like “Cytokine Storm” is that it reflects a convergence on a systemic inflammatory phenotype that, regardless of cause or context, may be amenable to “inflammo-stabilization.” CSS research must improve our appreciation of its various mechanisms and their interactions and treatments, but it must also identify the signs and interventions that may broadly prevent CSS-induced immunopathology.

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Section: Impaired Cytotoxic Functionmentioning

confidence: 99%

Section: Therapeutic T-cell Activation In Cancermentioning

confidence: 99%

Highways to hell: Mechanism-based management of cytokine storm syndromes

Canna

Cron

2020

Journal of Allergy and Clinical Immunology

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“…We postulated that other stimuli associated with changes in local intestinal and systemic IL-18 would also influence IEC MHCII expression. Repeated systemic stimulation through Toll-Like Receptor (TLR) 9 results in an inflammatory phenotype reminiscent of human macrophage activation syndrome (MAS), which increases serum IL-18 and is dependent on an IL-12-IFNg axis 16 , 25 – 27 . Repeated CpG administration induced high expression of MHCII on colonic and SI IECs ( Figure 6a ).…”

Section: Resultsmentioning

confidence: 99%

Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ

et al. 2021

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Major Histocompatibility Complex Class II (MHCII) is dynamically expressed on intestinal epithelial cells (IECs) throughout the intestine, but its regulation remains poorly understood. We observed that spontaneous upregulation of IEC MHCII in locally-bred Rag1 −/− mice correlated with serum Interleukin (IL)-18, was transferrable via cohousing to commercially-bred immunodeficient mice and could be inhibited by both IL-12 and IL-18 blockade. Overproduction of intestinal IL-18 due to an activating Nlrc4 mutation upregulated IEC MHCII via classical inflammasome machinery independently of immunodeficiency or dysbiosis. Immunodeficient dysbiosis increased Il18 transcription, which synergized with NLRC4 inflammasome activity to drive elevations in serum IL-18. This IL-18-MHCII axis was confirmed in several other models of intestinal and systemic inflammation. Elevated IL-18 reliably preceded MHCII upregulation, suggesting an indirect effect on IECs, and mice with IL-18 overproduction showed activation or expansion of type 1 lymphocytes. Interferon Gamma (IFNg) was uniquely able to upregulate IEC MHCII in enteroid cultures and was required for MHCII upregulation in several in vivo systems. Thus, we have linked intestinal dysbiosis, systemic inflammation, and inflammasome activity to IEC MHCII upregulation via an intestinal IL-18-IFNg axis. Understanding this process may be crucial for determining the contribution of IEC MHCII to intestinal homeostasis, host defense, and tolerance.

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“…IL-18 may be elevated in PAPA syndrome without increasing MAS risk for a variety of reasons. First, although ample animal work and preliminary case reports suggest otherwise 8, 14, 15 , it is possible that IL-18 elevation is associated with but not contributory to the pathology of either disease. Second, IL-18 typically functions by amplifying the effects of other cytokines, and it may operate in a substantially different inflammatory context in PAPA than SJIA- and NLRC4-MAS.…”

Section: Discussionmentioning

confidence: 99%

Excess Serum Interleukin-18 Distinguishes Patients with Pathogenic Mutations in PSTPIP1

Stone

Ombrello

Aróstegui

et al. 2021

Preprint

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Objective: Dominantly-inherited mutations in PSTPIP1 cause a family of monogenic autoinflammatory diseases epitomized by Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome. The connections between PSTPIP1 and PAPA are poorly understood, although in vitro evidence suggests increased activation of the pyrin-inflammasome. We sought to identify biomarkers of potential mechanistic, diagnostic, and therapeutic utility specific to autoinflammatory diseases. Methods: Clinical and genetic data and sera were obtained from patients referred with concern for PAPA syndrome, as well as relevant disease controls. Serum Interleukin-18 (IL-18) and related biomarkers were assessed by bead-based assay and ELISA. Results: Symptoms in PSTPIP1 mutation-positive PAPA patients overlapped with those of mutation-negative PAPA-like patients, but the former were younger at onset and had more arthritis. We found uniform elevation of total IL-18 in PAPA patients at a level approaching NLRC4-associated Macrophage Activation Syndrome (MAS) and well beyond Familial Mediterranean Fever. IL-18 elevation in PAPA patients' sera persisted despite fluctuations in disease activity. IL-18 Binding Protein (IL-18BP) was modestly elevated, and as such PAPA patients had detectable free IL-18. PAPA patients did not develop MAS, and CXCL9 (an indicator of Interferon-gamma activity) was rarely elevated in their sera. Conclusion: PAPA syndrome is a refractory, and often disabling monogenic autoinflammatory disease associated with chronic elevation of serum IL-18, but not risk for MAS. This finding instructs our understanding of the origins of excess IL-18, its potential spectrum of pathogenic effects, and the possible role for IL-18 blockade in refractory PAPA syndrome.

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Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation

Cited by 32 publications

References 55 publications

Highways to hell: Mechanism-based management of cytokine storm syndromes

Highways to hell: Mechanism-based management of cytokine storm syndromes

Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ

Excess Serum Interleukin-18 Distinguishes Patients with Pathogenic Mutations in PSTPIP1

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